SV40 large T antigen (TAg) contributes to cell transformation, in part, by targeting two well characterized tumor suppressors, pRb and p53. TAg expression affects the transcriptional circuits controlled by Rb and by p53. We have performed a microarray analysis to examine the global change in gene expression induced by wild-type TAg and TAg-mutants, in an effort to link changes in gene expression to specific transforming functions. For this analysis we have used MEFs expressing TAg or infected by SV40. Our analysis indicates that TAg can induce interferon-stimulated genes in MEFs and that this induction depends upon the LXCXE motif and p53 binding.
Induction of interferon-stimulated genes by Simian virus 40 T antigens.
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View SamplesSV40 transforms cells through the action of two oncoproteins, large T antigen and small t antigen. Small t antigen targets phosphatase PP2A, while large T antigen stimulates cell proliferation and survival by action on multiple proteins, including the tumor suppressors Rb and p53. Large T antigen also binds components of the transcription initiation complex and several transcription factors. We examined global gene expression in SV40-transformed mouse embryo fibroblasts, and in enterocytes obtained from transgenic mice. SV40 transformation alters the expression of approximately 800 cellular genes in both systems. Much of this regulation is observed in both MEFs and enterocytes and is consistent with T antigen action on the Rb-E2F pathway. However, the regulation of many genes is cell-type specific, suggesting that unique signaling pathways are activated in different cell types upon transformation, and that the consequences of SV40 transformation depends on the type of cell targeted.
Cell-type specific regulation of gene expression by simian virus 40 T antigens.
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View SamplesThe E2F family consists of transcriptional repressors and activators that control cell proliferation. In the classic paradigm of cell cycle regulation, the three activators, E2F1, E2F2 and E2F3, are invariably depicted as the final components of a CDK/Rb signaling cascade that executes the transcriptional program necessary to commit cells to enter S phase.
Cell proliferation in the absence of E2F1-3.
Specimen part
View SamplesThe retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1G) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1G/G MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1G/G MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1G/G cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1G/G MEFs is responsive to p16 expression, indicating that the G-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1G/G mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear normal while being accompanied by derepression of pRB regulated E2F targets. This suggests that non-E2F, pRB dependent pathways may have a more relevant role in proliferative control than previously identified.
A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles.
Specimen part
View SamplesCombined ablation of Myc and E2f1-3 results in disruption of crypt-villus integrity in the small intestine due to a S-G2 cell cycle blockade.
Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles.
Specimen part
View SamplesLoss of Myc corrects abrrant transcription in Rb KO villi, while these genetic manipulation does not lead to major gene expression changes in crypts.
Redeployment of Myc and E2f1-3 drives Rb-deficient cell cycles.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
E2f8 mediates tumor suppression in postnatal liver development.
Age, Specimen part
View SamplesE2Fs are regulators of the cell cycle and are involved in development. In this study we examine transcriptional changes occurring the liver in E2f1 (1KI) and E2f3b (3bKI) knock in mice. These mice have E2f1 or E2f3b knocked into the E2F3a locus resulting in loss of E2f3a and expression of E2f1 or E2f3b from the E2f3a locus as originally described In Tsai et. al., Nature 2008.
E2f8 mediates tumor suppression in postnatal liver development.
Age, Specimen part
View SamplesE2Fs are regulators of the cell cycle and are involved in development and hepatocellular carcinoma. In this study we examine transcriptional changes occurring the liver in E2f1 (1KI) and E2f3b (3bKI) knock in mice. These mice have E2f1 or E2f3b knocked into the E2F3a locus resulting in loss of E2f3a and expression of E2f1 or E2f3b from the E2f3a locus as originally described In Tsai et. al., Nature 2008.
E2f8 mediates tumor suppression in postnatal liver development.
Age, Specimen part
View Samples